DNA Methylation Declines with Age

Aging is associated with loss of an epigenetic marker that helps control gene expression, according to new research published today (June 11) in Proceedings of the National Academy of Sciences, with a centenarian carrying some 7 percent fewer methylated DNA bases than a newborn. Researchers posit that reductions in methylation may be one of the mechanisms underlying the aging process.

“It’s one of the first studies to look at aging from an epigenetic point of view,” said Willis Li, at the University of California, San Diego, who did not participate in the research. Other research, including Li’s own in Drosophila, has shown that the amount of heterochromatin—histone modifications that result in tight chromosome packing—also appears to decline with an organism’s age. The new study further supports the idea that epigenetic modifications, in addition to genetic factors, play a critical role in aging, said Li.

Searching for clues to why some people live long healthy lives and some succumb to early to aging, scientists have discovered that genetic factors only contribute about 10 percent to longevity, while environmental factors contribute about 90 percent, said senior author Manel Esteller of the University of Barcelona. Knowing that epigenetic modifications, such as cytosine methylation, are responsive to environmental stimuli, Esteller and his collaborators wondered if they could be a reliable indicator of physiological aging.

The scientists first compared the DNA methylation epigenome—the genome-wide level and location of methylated cytosines located next to guanines (CpG)—in circulating T cells from a newborn and a centenarian. The general level of methylation of the centenarian’s genome (73 percent), they found, was lower than the newborn’s (80 percent). Looking at a 26-year-old’s genome, they found an intermediate level of methylation.

Examining more closely the patterns of methylation in the newborn’s and centenarian’s genomes gave hints that Esteller thinks may help explain how loss of methylation affects cellular function and leads to aging. While most areas of the centenarian’s genome were less methylated—such as genes with tissue-specific expression patterns, suggesting the possibility that the centenarian’s T cells were expressing genes they shouldn’t, like neuron- or testes-restricted genes—a few regions showed greater methylation. Many promoters of tumor-suppressor genes, for example, showed higher levels of methylation, suggesting a possible connection with age-associated increases in cancer risk, Esteller said.

When Esteller and his colleagues extended the study to 19 more newborns and 19 people in their 90s, they found similar differences in their genomes’ methylation patterns. Furthermore, explained Esteller, they were able to use the epigenetic patterns to predict the age—newborn or nonagenarian—of their samples.

As tantalizing as these differences are, it’s still not clear how the epigenetic changes factor into the aging process, said Karl Kelsey, a molecular biologist who studies epigenetic biomarkers for cancer at Brown University, who was not involved in the study. “We don’t yet fully understand the phenotypic consequences of epigenetics,” he said, and “it’s unclear what’s underlying the loss [of methylation].”

It could be that DNA methyltransferases become less active as age progresses, for example, adding fewer methyl groups after each cell division. Alternatively, changes in metabolism and diet could change the intake of folate, the nutrient from which the methyl groups are derived. Understanding the mechanism of these epigenetic changes, as well as their consequences, will be an important next step for understanding how the new findings relate to aging, Kelsey said.

In the meantime, Esteller hopes to discover whether manipulating the epigenome of mice will extend their lifespans. If maintaining methylation really can stave off aging, it may offer therapies for preventing neurodegenerative disorders, he said, and possible aid children suffering from premature aging disorders, who show epigenetic changes similar to the nonagenarians’.

Much remains to be explained, said Li, but “more and more people are aware of the epigenetic impact factor on aging.”

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Anonymous

June 12, 2012

For any study to be conducted on humans, it would be difficult-to-impossible to rule out variances in exposure to experience differences, to ascertain that aging alone is a determinant of differences found. To compare subject of the same age from one geographical area to another (provided they live there all their lives), who work in different occupations, who tend to eat certain diets, who do or do not engage in strenuous exercise...

Wow! What a challenge to account for all the variances among experience factors.

The question which comes up here is can we account for all such variances. The answer would be not likely. It is for fact that even identical twins (exposed to same living environments) are bound to have high rated differences in their methylation patterns. Agreed that all this have a part in the ageing and research methodologies can only try to approximate to the most closest level and always there is a variance associated with such experimentation. The key thing to note is whether the results are reproducible or not. If we take different set of people keeping all the other experimental parameters fixed (including environmental factors) then we are bound to come approximately the same set of results.Â

Very wise observation.Â Error encounters error, and can reinforce error such that it becomes obvious that it is cumulative noise, and thus can, by that very characteristic draw attention to itself and be tuned out or, at the other end of the continuum, error can sometimes cancel error, with either result leading to our being enabled to identify a clearer residual cameo, as it were, whereby what is significant stands out boldly in contrast to what is not significant.Â

Come to think of it, what you share here tends to parallel the non-intuitive manner in which Fourier transforms disclose significant patterns of light absorption.Â Also, come to think of it, the iterative progress of expanding ever diminishing reproductions of fractals is more efficient, in an electronic logic program, than any algebra or geometry could measure.Â A computer logic program, applying fractals, can, for example, determine the length of the border of an irregular two-dimensional object, or its area -- or can determine the area of the outside of a cell, or the volume of its contents, say -- to any degree of mathematical precision (limited only by the accuracy of our measurings, of course) -- that would meet with our research need.Â Â Â

By this stimulating reply, you have increased my awareness of how and why so many advances at the frontiers of the sciences today (including the bio-sciences) are increasingly data-driven, in increasing proportion to the extent to which hypothesis-driven.

This is something I have intuited and had been seeking a way to articulate to others and, suddenly -- with your reply to me, above -- you triggered in my thinking an epiphanical clear picture of how to express it.

That done, you now have me thinking about why it is essential that data banks be designed to "talk the same language," lest the merging of one experimental data result with that of another data bank, differently formatted, would find the two incompatible. Of course, on the other side of that coin, we must always seek to identify instances of our quite human tendency unintentionally to build into our interpretive algorithms artifactual patterns reflecting unconscious motives, such as the motive to conserve, say, some doctrine with which we have unconsciously become indoctrinated. But it is conceivable that EVEN THAT might be "recognized" by application of error-correction algorithms.

(Ironically, some of the benefits and some of the harms that result from the human cell's error correction mechanism seem to result in deleterious effects, and some of the very mechanisms whereby adaptation would be achieved by way of diversification within the human genome seem to result in deleterious effect, and some of the very mechanisms whereby the human physiology would seek to defend against pathogens and parasites seem to attack their own host. But this digresses from the main point I wish to make here.)

By extension of your input here, even studies applying different hypotheses to a study of the same population, or applying the same hypothesis to many different populations, could very well expose, serendipitously, patterns of significances versus insignificances that no researcher had even been looking for.

What a stimulating observation you have just provided to me.

Isn't it wonderful that this forum makes possible the sharing of such a catalytic stimulus to another person's thinking.

The observation that DNA methylation decreases with Age ,how this information can help in tackling the problem of aging. What are the factors which reduce DNA methylation ? What are other sources of methyl group other than folate?

Why DNA Methylation Declines With AgeÂ Â DNA methylation declines with age most probably due to RNAs activity decline with age most probably due to decline with age of the circumstantial pressure for physiological adaptation for natural selectionâ€¦Â A.a)DNA Methylation Declines With Agehttp://the-scientist.com/2012/...Â b)1)â€œRNA molecules are synthesized in the cell nucleus, yet many have to be moved to the cytoplasm to be processed and/or to effect their function. Different classes of RNA are transported from the nucleus by different transport systems.â€쳌Â 2)â€쳌 Brain volume tended to decrease with subjects' age, consistent with other studies that have found that some brain shrinkage occurs normally as people grow older. But among cocaine users, the rate of shrinkage was almost twice that of the non-drug-using group (about 3 milliliters per year versus 1.7 milliliters for the non-drug-users)â€쳌Â B.FromÂ â€œMore On Evolution In The Still RNA World â€œhttp://classic.the-scientist.c...Â â€¦Rational possibility that the RNAs are the environmental feedback communicators to, and modifiers of, the genomes, the effectors of the desirable biased genes expressions modifications, of enhanced energy constraining for survival. Dov Henis (comments from 22nd century) http://universe-life.com/2012/...Â

I am wondering why my comment posted three days ago is still not been shown.Â In my comment I provided a title of my previous publication very relevant to this "new" discovery and an URL for aÂ web pageÂ listing some of my publications on aging.To promote scientific discussion and to search for pioneering discovery I encourage people to Google for "Shi V. Liu Aging".I hope my such comment would not be hidden again.